CZ300465B6 - Process for preparing compressed pharmaceutical formulation containing tibolone - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing compressed pharmaceutical formulation with the active substance tibolone by direct compression into tablets, whereas during the preparation process the formulation is subjected to the action of a protic solvent, either by addition of 0.1 to 3 percent by weight of this solvent in the liquid state and/or in the vapor form by ensuring the ambient atmosphere with the contents of solvent vapors above 50 percent relative.

Description

A method of making a compressed pharmaceutical formulation comprising tibolone

Technical field

The invention relates to compressed formulations containing tibolone.

BACKGROUND OF THE INVENTION

Preparations containing tibolone, chemically 17β-hydroxy-17α-ethynyl-7α-methylestr-5 (10) -en-3one, belong to a group of medicines called hormone replacement therapy (HRT). These products are used in menopausal women when the female body stops producing the estrogen hormone. The products alleviate the symptoms associated with menopause and stop the bone loss process.

During manufacture and storage of products containing tibolone a certain amount of degradation product - isotibolone (Δ ⁴ - tibolone; 17 | 3-hydroxy-l 7a-ethynyl-7a-methylestr-4-ene-3-one). Isotibolone is a thermodynamically stable isomer of tibolone, which is produced by isomerization of the double bond of tibolone. Isotibolone is also an important metabolite in the blood of patients taking tibolone-containing products.

Thermodynamically more stable isotibolone is one of the problem impurities and a lot of effort has been devoted to creating a stable tibolone composition, where isotibolone would only be produced to a limited extent.

Reduction of this impurity in the active substance is discussed in N.P. van Vieta et al., Red. Trav. Chim. Pays Bas 105: 111-115 (1986). The production process described herein obtains tibolone with an isotibolone content of less than 1%.

Patent application EP 1 121 375 describes a process for the production of tibolone which results in a product with very good stability. By the described process, a product with a low isotibolone content of less than 0.5% can be obtained. Pharmaceutical formulations containing this impurity content are made of a so-called basic granulate to which tibolone is admixed and subsequently the mixture is tabletted. This basic granulate is previously produced by wet granulation containing 5.5 to 7% water, preferably 6%.

It has been shown in patent application WO98 / 47517 that it is preferable to maintain the formulation at higher humidity, i.e. 50 to 70% relative humidity, for product stability. In Example 5 of this application, the stability of the product at different storage at different humidity is compared. At 25% RH, the isotibolone content reached 13% after 3 months of storage, while at 75% RH, only 3%.

However, it has been shown that even when these conditions are accepted and the direct tabletting technology, i.e. the substance produced according to EP 1 121 375, when stored under the conditions according to WO 98/47517, the impurity of tibolone increases rapidly in the first days after the finished pharmaceutical substance.

SUMMARY OF THE INVENTION

The present invention provides a process for the manufacture of a compressed pharmaceutical formulation with the active ingredient tibolone by direct tabletting, wherein the formulation is exposed to an anti-solvent during manufacture. This action of the protic solvent is realized in such a way that either in the course of

The preparation process adds 0.1 to 3% by weight, preferably 0.5 to 1.5% by weight, of a protic solvent to the dry mixture, or the concentration of protic solvent vapor is maintained above 50% during the preparation of the compressed formulation; preferably in the range of 50 to 65%, optionally by a combination of both.

The pharmaceutical formulation thus produced is significantly more stable than the prior art formulations immediately after manufacture. The pharmaceutical formulation thus prepared containing 0.25 to 10% by weight of tibolone, preferably 2 to 5% by weight of tibolone, will allow the isotibolone content to not increase by more than 5% in standard stability tests at 25 ° C and 60 ± 5% relative humidity. 0.4% based on the area of the tibolone peak over a period of 1 month. Preferably, it does not increase by more than 0.2% based on the area of the tibolone peak over a period of 1 month.

DETAILED DESCRIPTION OF THE INVENTION

The direct tabletting process is a technological process in which the excipients are gradually sieved and mixed in several steps with the active ingredient so as to result in a sufficiently homogeneous mixture of ingredients. This process does not use granulation, which in turn uses a binder solution in a suitable solvent to form granules which are then dried. The direct tabletting process is advantageous in its simplicity and gentleness on thermolabile substances which may undergo decomposition during drying.

In direct tableting experiments with tibolone, it has been shown that a composition with a very low content of the most problematic isotibolone impurity can be prepared. If the starting material was used with an isotibolone content of less than 0.1%, the content immediately after processing did not increase to more than 0.2%. This value very well corresponded to the values published for alternative granulation processes where the isotibolone content was less than 0.7%.

The problem was, however, an increase in this impurity during the first days of storage of the tablets so produced.

For example, it has been shown that by using the direct tabletting technique without any modification, about half of this month's impurity is produced in the first 3 days of storage.

Surprisingly, it has been shown that this problem must be solved already during pharmaceutical production by exposing the material to protic solvent during processing.

The protic solvent capable of proton (H ⁺ ) release may be alcohols. Especially lower C1 to C4 alcohols. The alcohols methanol, ethanol or isopropanol are preferred. Ethanol is preferred for this general availability and low toxicity. A particularly preferred protic solvent is water. It is a substance that is neither toxic nor flammable and generally available (yet).

The protic solvent may act in both liquid and gaseous phases or a combination of both.

To utilize the solvent in the liquid phase, 0.1 to 3%, more preferably 0.5 to 1.5% by weight of the protic solvent is added to the mixture during manufacture of the formulation by direct tabletting.

If the protic solvent is used in the gas phase, production is carried out in an atmosphere containing more than 50% relative solvent vapors. The percentages are relative to the second component of the atmosphere, which is usually air. An atmosphere composition of 50 to 65% relative vapors is preferred. For the use of the solvent in the gas phase, water is particularly advantageous for the modest performance and the aforementioned properties such as non-flammability and non-toxicity.

In the following detailed description of the ingredients used, all percentages are by weight.

-2GB 300465 B6

Typically, 10 to 95% of a filler selected from lactose monohydrate, anhydrous lactose, microcrystalline cellulose, corn or potato starch, dibasic calcium phosphate, sorbitol or mannitol is used to produce the pharmaceutical composition of the invention.

Preferably, the disintegration properties of the starch are utilized and a mixture of starch and lactose is used. The preferred ratio is 1: 1 to 1:10.

The resulting composition may contain, for example, 10 to 95% lactose and at the same time 1 to 30% starch. In place of lactose, sugar alcohols such as mannitol or sorbitol may be used in the compositions. In these compositions starch acts as a disintegrant.

If microcrystalline cellulose is used as a filler, the amount is 10 to 90%, and the disintegration properties of the cellulose can also be utilized.

Calcium hydrogen phosphate is recommended for use in amounts of 10 to 60%.

The composition may contain glidants-lubricants, for example of the stearate type such as magnesium stearate 0.1 to 5%.

It may contain other stabilizing agents such as antioxidants, for example ascorbyl palmitate in an amount of 0.1 to 1%.

A more detailed embodiment of the process according to the invention is indicated in the following variants. In the following variations of the production process, components such as filler, disintegrant, stabilizer, lubricant, are contemplated, with some substances having multiple functions. It is shown to be significant in which phase and how the compositions are exposed to the protic solvent.

Procedure 1

Tibolone is mixed with part of the filler and stabilizer. The resulting mixture is mixed in a second stage with the disintegrator and the second part of the filler and to this mixture is added a protic solvent in the liquid state. The solvent is dispersed as evenly as possible throughout the mass, which can preferably be accomplished by sieving the moistened mixture through a suitable sieve (e.g., a mesh size of 0.5 to 2.0 mm) and then stirring the mixture. A lubricant is added to the resulting mixture and mixed.

Procedure 2

Tibolone is mixed with part of the filler and stabilizer. The resulting mixture is mixed with another portion of filler and disintegrant. A lubricant is added to the resulting mixture and the whole is mixed. The protic solvent in the liquid state is then added to this mixture. The solvent is dispersed as evenly as possible throughout the mass, which can be preferably carried out by sieving the moistened mixture through a suitable sieve (mesh size 0.5-2.0 mm) and subsequently stirring the mixture. The result is a tablet ready for tabletting.

Procedure 3

To a portion of the filler and disintegrant is added a protic solvent in the liquid state. The solvent is dispersed as evenly as possible throughout the mass, which can be accomplished by sieving the moistened mixture through a suitable sieve (mesh size 0.5-2.0 mm) and then stirring the mixture. In particular, tibolone is mixed with part of the filler and stabilizer. The resulting mixture is mixed with a moistened portion of the batch-filler and disintegrant. Lubricant is added to the resulting wetted mixture and the whole is mixed. The result is a tablet ready for tabletting.

-3 CZ 300465 B6

Procedure 4

The entire production process, including tabletting, takes place in an environment with a relative humidity of more than 50%, preferably 50 to 65%. Those were he mixes with part-filler and stabilizer. The resulting mixture is mixed with another portion of filler and disintegrant. A lubricant is added to the resulting mixture and the whole is mixed. The result is a tablet ready for tabletting.

In the following, all percentages are by weight unless otherwise indicated.

The present invention also provides a tablet of preferred stability properties containing 0.25 to 10% tibolone, more preferably 0.25 to 3% tibolone, with 80 to 90% lactose monohydrate and 0.1 to 3%, preferably 0.5 to 1%. 5% free water, not water bound in the crystal of solid ingredients. The tablet preferably contains 7 to 12% starch to improve disintegration properties.

Another characteristic of the formulation of the invention is its behavior under the standard stability test conditions described in Pharm. Eur. Formulations of the invention containing 0.25 to 3% tibolone after one month storage at 25 ° C and 60 ± 5% relative humidity will allow nes20 to increase the isotibolone content by more than 1%, more preferably 0.4%, even more preferably 0 , 2%. The isotibolone percentages in this case are calculated from the ratio of peak areas of tibolone to isotibolone measured by a standard HPLC method.

Example 1

1. Product composition without addition of water, lot 1

Name of the substance Quantity (g) Specifications Active substance Tibolon 250 In-house specification Excipients Lactose monohydrate 8 700 Ph.Eur. Potato starch 950 Ph.Eur. Askorbyl palmitate 50 Ph.Eur. Magnesium stearate 50 Ph.Eur.

Mean tablet weight 100 mg (95-105 mg).

-4GB 300465 B6

2. Composition with addition of water

Name of the substance Quantity (g) Specifications Active substance Tibolon 250 In-house specification Excipients Lactose monohydrate 8 700 Ph.Eur. Potato starch 950 Ph.Eur. Askorbyl palmitate 50 Ph.Eur. Magnesium stearate 50 Ph.Eur. Purified water 100 ALIGN! PhEur

Mean tablet weight 100 mg (95-105 mg).

Process description:

Tablet blend product without adding water - batch 1

Direct tabletting technology is used as the most suitable process for production. The raw materials are weighed, sieved and homogenized in three stages. In the first step, the active ingredient, ascorbyl palmitate and a portion of lactose are mixed for 15 minutes. In the second stage, the first portion is screened together with the rest of the lactose and potato starch. Sieved magnesium stearate is further added to the mixture and the resulting mixture is homogenized for a further 5 minutes.

Tableting product with addition of water - batch 2

The procedure is the same as for batch 1 except that 1% by weight of water, i.e. 100 g per 10 kg of the mixture, is added to the mixture before the final homogenization 20.

In both cases, the mixture was tabletted into a flat round tablet of 6 mm diameter. Production conditions: at 20 to 25 ° C and 30 to 40% RH.

Stability tests

Conditions 25 ° C, 60 ± 5% RH

5GB 300465 B6

Test time Product without water Batch 1 Product with addition of water Batch 2 Impurity concentration - [%] * Impurity concentration - [%] * HT HPT IT HT HPT IT Day 0 (day of batch production) 0.08 0.02 0.14 0.03 0.06 0.11 Day 1 0.07 0.02 0.41 0.04 0.06 0.12 Day 3 0.04 0.07 0.55 0.05 0.07 0.14 Den 10 0.08 0.08 0.70 0.07 0.08 0.17 Den 30 0.09 0.09 1.18 0.10 0.08 0.24

Meaning of abbreviations:

HT-10-hydroxytibolone HPT-10-hydroxyperoxytibolone

IT - isotibolone (A -tibolon ⁴⁾ *% peak area vztaženého desktop tibolone peak detector UV DAD

Discussion:

The data show that water significantly reduces the conversion of tibolone to isotibolone. It has no significant effect on the formation of the other two impurities.

Example 2 15

Batch 3 had the same composition and was prepared by the same procedure as Batch 1, but the conditions were maintained as follows: temperature 20-25 ° C and relative air humidity 55-65% (for batch 1:30-40%).

Stability tests

Conditions 25 ° C, 60 ± 5% RH

Test time Batch product Product Batch 3 Impurity concentration - [%] * Impurity concentration - [%] * HT HPT IT HT HPT IT Day 0 (day of batch production) 0.08 0.02 0.14 0.03 0.06 0.21 Day 1 0.07 0.02 0.41 0.03 0.07 0.32 Day 3 0.04 0.07 0.55 0.04 0.09 0.35 Den 10 0.08 0.08 0.70 0.08 0.10 0.34 Den 30 0.09 0.09 1.18 0.15 0.09 0.47

-6GB 300465 B6

Discussion:

The example shows that when production is carried out at higher relative humidity (55-65%), conversion to isotibolone under comparable conditions is slower than at lower humidity (30-40%). Changing the conversion rate to other products is not significant.

EXAMPLE 3 Batch 4 was produced in the same manner as Batch 1, but during both production and stability tests, the composition was formed and stored in a nitrogen atmosphere with a maximum water content of 5 ppm.

Stability test

-Batch 1 20-25 ° C, 30-40% RH.

- Lot 4 20-25 ° C, nitrogen atmosphere (less than 5 ppm water)

Test time Batch product Batch product 4 Impurity concentration - [%] * Impurity concentration - [%] * HT HPT IT HT HPT IT DenO (day of batch production) 0.08 0.02 0.14 0.04 0.02 0.15 Day 1 0.07 0.02 0.41 0.04 0.03 0.45 Day 3 0.04 0.07 0.55 0.05 0.04 0.66 Den 10 0.08 0.08 0.70 0.04 0.08 2.00 Den 30 0.09 0.09 1.18 0,07 ** 0,09 ** 2.77 **

** After 24 days.

Discussion:

The data show that further reduction of the water content in the production atmosphere leads to an increase in the conversion rate to isotibolone. The effect on other impurities is not significant.

Example 4

Batch 5 was produced by the procedure of Batch 2, but absolute ethanol 30 was used instead of water in an amount of 1% by weight based on the batch size.

Compositions with the addition of absolute ethanol:

-7EN 300465 B6

Name of the substance Quantity (g) Specifications Active substance Tibolon 250 In-house specification Excipients Lactose monohydrate 8 700 Ph.Eur. Potato starch 950 Ph.Eur. Askorbyl palmitate 50 Ph.Eur. Magnesium stearate 50 Ph.Eur. Absolute ethanol 100 ALIGN! PhEur

Mean tablet weight 100 mg (95-105 mg). 5 Stability tests

Conditions 25 ° C, 60 ± 5% RH

Test time Batch product Product of lot 5 Concentration impure t - [%] * Concentration impure HT HPT ΓΓ HT HPT IT Day 0 (day of batch production) 0.08 0.02 0.14 0.05 0.02 0.09 Day 1 0.07 0.02 0.41 0.09 0.07 0.11 Day 3 0.04 0.07 0.55 0.05 0.04 0.12 Den 10 0.08 0.08 0.70 0.04 0.08 0.14 Den 30 0.09 0.09 1.18 on. on. on.

Discussion:

The data show that further use of ethanol as well as the use of water in production leads to a significant slowdown in the conversion rate to isotibolone. The effect on conversion to other impurities is not significant.

Claims (19)

PATENT CLAIMS A process for the production of a compressed pharmaceutical formulation with the active substance tibolone by direct tableting, characterized in that during manufacture the formulation is exposed to a protic solvent, either by adding 0.1 to 3 wt. of this solvent in the liquid state and / or in the form of a vapor by providing an ambient atmosphere with a solvent vapor content greater than 25 50% relative. -8GB 300465 B6 Process according to claim 1, characterized in that water is used as a protic solvent. 5 The process according to claim 1, characterized in that an organic protic solvent selected from C1 to C4 alcohols is used. The process according to claim 3, wherein the protic solvent is ethanol. Process according to any one of the preceding claims, characterized in that the protic solvent is added in the liquid state to the intermediate prior to compression. The method of claim 5, wherein the protic solvent is added to either one of the excipients, the excipient mixture, or the mixture of excipients and tibolone. Method according to claim 6, characterized in that the protic solvent is added in liquid form to the directly tabletable mixture and is compressed after homogenization. 20 May Process according to any one of claims 5 to 7, characterized in that a protic solvent is used in an amount of 0.5 to 1.5% by weight. Method according to claim 2, characterized in that the production process of the tablets is conducted at a relative ambient humidity of 50 to 65%. A process according to any one of the preceding claims, characterized in that 10 to 95 wt. the composition comprises a filler selected from the group consisting of lactose, lactose monohydrate, microcrystalline cellulose, potato starch, corn starch, dibasic calcium phosphate, sorbitol, mannitol, and mixtures thereof. Process according to Claim 10, characterized in that lactose or starch is used as the filler. The method of claim 10, wherein the tablet comprises starch and lactose 35 in a ratio of 1: 1 to 1: 10. 13. A tablet obtained by the method of claim 1 comprising 0.25 to 10 wt. % tibolone, 80 to 90 wt. lactose monohydrate and 0.1 to 3% free water. 40 14. The tablet of claim 13, further comprising 7 to 12 wt. starch. 15. A tablet according to claim 13 or 14 comprising 0.5 to 1.5 wt. free water. A solid pharmaceutical formulation containing 0.25 to 3 wt. tibolone, obtained by the method of claim 1, wherein after one month of storage at 25 ° C, 60 ± 5% relative humidity, the isotibolone content does not increase by more than 1% of the isotibolone and tibolone peak area in a standard HPLC method. The pharmaceutical formulation according to claim 16, wherein the isotibolone content does not increase by more than 0.2% area ratio after monthly storage under given conditions. 18. A pharmaceutical formulation according to claim 17 comprising from 80 to 80 55 90 wt. lactose monohydrate. -9EN 300465 B6 The pharmaceutical composition of claim 18, further comprising 7 to 12% starch.